1alpha-halomethyl-16, 17-acetals and ketals of the pregnane series and intermediates therefor



United States Patent C) 3,231,569 Iu-HALOMETHYL-16,17-ACETALS AND KETALS OF THE PREGNANE SERIES AND INTERME- DIATES THEREFOR Gerald W. Krakower, Elizabeth, N.J., assignor to Olin Mathieson Chemical Corporation, New York, N. Y., a corporation of Virginia No Drawing. Filed May 19, 1964, Ser. No. 368,711 5 Claims. (Cl. 260-43955) This invention relates to and has 'as its object the provision of novel physiologically active steroids, processes for their production and new intermediates useful in the preparation thereof.

More particularly, this invention relates to the provision of compounds of the formula X is halogen (e.g., chloro, fluoro, bromo and iodo); P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl; Q is selected from the group consisting of lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl; or together with the carbon to which they are joined P and Q is a monocyclic cycloalkyl or monocyclic 'heterocyclic radical.

The products or" this invention are physiologically active substances which possess progestational activity when administered both in the form of tablets and as a solution or suspension and hence can be used in. lieu of known Ice progesta-tional agents, such as progesterone, in the treatment of habitual abortion. For this purpose, they can be administered in the same manner as progesterone, for example, the dosage being adjusted for the relative potency of the particular steroid. The compounds of this invention can also be administered perorally in the form of tablets.

The compounds of this invention can be prepared by the process of this invention, entailing a number of steps starting with compounds of the formula wherein R may be hydrogen aryl or lower alkyl, and P and Q are as hereinbefore defined.

The starting materials of this invention may be prepared according to the teachings and disclosures of copending application, Serial No. 330,583, filed December 16, 1963, now U. S. Patent 3,174,971 in the names of Gerald W. Krakower and Josef Fried.

The compounds of this invention may be prepared by the processes of this invention employing the starting materials set forth hereinabove. The process of this invention may be represened by the following equations wherein X, R, P and Q are as hereinbefore defined:

In the first step of the instant invention, the 101,20- cyclopropane starting materials (Compounds A) are oxidized as by treatment with a perbenzoic acid, for example, rn-chloro perbenzoic acid to yield the 6ot,7a-0 X id0 derivatives (Compounds B) of the starting material. Compounds B are new compounds of this invention.

Compounds B may then be treated to directly yield the 1-ha1omethyl-6-halo derivatives (Compounds D), which are new compounds of this invention, as by treatment with an excess of hydrohalic acid, e.g., hydrochloric or hydrobrornic acid at an elevated temperature. Alterna- 6oz,7oc-0xid0-1oz,2ot-methylene-I60:,1 7ocdimethylmethyl enedioxy -A -pregnene-3,2 O-dione A solution of 1.00 g. of la,2ot-methylene-l6a,l7a-(dimethylmethylenedioxy)-A -pregnadiene-3,20 dione and 2.15 g. of m-chloroperbenzoic acid in 25 ml. of methylene chloride is left at room temperature for twenty-two hours. The reaction mixture is diluted with methylene chloride to a volume of 150 ml. and then washed with five 100 ml. portions of 5% potassium carbonate, two 100 ml. portions of water, 100 ml. of 5% potassium iodide solution, 100 ml. of water, two 100 ml. portions of 5% sodium sulfite solution, 100 ml. of water, dried, and evaporated to give 985 mg. of crude product. Recrystallization from methanol gives 679 mg. of 6a,7b-oxido-lale-methylene- .16a,17a (dimethylmethylenedioxy) A pregnene-3,20-

dione, M.P. 260262 C. [a] +2257".

Analysis.--Calcd for C H O C, 72.79; H, 7.82. Found C, 72.65; H, 7.80.

Similarly, substituting la,2u-diphenylmethylene-l6a, 17a-(dimethylmethylenedioxy) A pregnadiene 3,20- dione for 1u,2u-methylene-16a,Hot-(dimethylmethylenedioxy) -A -pre gnadiene-3,20-dione and following the procedure of Example 1, there is obtained 6a,7oz-OXid0-1a,2ocdiphenylmethylene 16a,17a (dimethylmethylenedioxy)- A -pregnene-3,20-dione.

EXAMPLE 2 6-c hl0ro-1 a-chloromethyl-I ,1 7oc- (dimethylmethylenedioxy -A -pregnadiene-3,20-di0ne Further recrystallization gives analytically pure, material,

. 4- 115 mg. of an oil. Crystallization from methanol gives 75 mg. of 6fl-chloro-la,2a-methylene 16a,l7u-(dimethylmethylenedioxy)-A -pregnene-7a-ol3,20-dione, M.P. 237- 239 C. A further recrystallization raised the melting point to 238-2395 0., [04] +198.3,

Max.

Similarly, following the procedure of Example 3, but substituting ,7u oxido 1a,2a-diphenylmethylene-16a, 17a-(dimethylmethylenedioxy) -A -pregnene 3,20 dione for 6a,7ot oxido 1a,2a methylene-16a,17a-(dimethylmethylenedioxy)-A -pregnene-3,20-dione there is obtained chloro 1a,2u-diphenylmethylene-l6a,17a-(dimethy1- methylene dioxy) -A -pregnene-3 ,ZO-dione.

Similarly, substituting equivalent amounts of hydrogen bromide or hydrogen fluoride for the hydrogen chloride of Example 2, the respective bromo or fluoro derivatives are obtained.

EXAMPLE 4 6-chloro-1 a-chloromethyl 6a,] 7u-(dimethylmethylenedioxy -A -pregnadiene-3,2O-diorze Following the procedure of Example 2 but substituting 6,8 chloro 111,20: methylene l6tx,l7 x(dimethylmethylenedioxy)-A -pregnene-7a-ol-3,2O-dione for 6u,7u-oxidolulu-methylene in 16oz,l7a-(dimethylmethylenedioxy)- A -pregnene-3,20-dione there is obtained 6-cl1loro-lachloromethyl l6u,l7a (dimethylmethylenedioxy)A pregnadiene-3,20-dione. I V

This invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound selected from the group of steroids consisting of the compounds of the formula wherein each R is selected from the group consisting of hydrogen, lower alkyl and aryl; R is selected from the group consisting of hydrogen and acyl; X is halogen; P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; Q is selected from the group consisting of lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl,

' monocyclic aryl lower alkyl, monocyclic heterocyclic and Analysis-Calcd for 0 11 0 01 0, 64.23; H,"6.90;

Cl, 15.17. Found: C, 64.56; H, 6.88; Cl, 15.69.

Similarly, substituting equivalent amounts of hydrogen bromide or hydrogen fluoride for the hydrogen chloride of Example 2, the respective bromo or fluoro derivatives are obtained.

EXAMPLE 3 fifi-chloro-Iac,2a-methylene 16u,17u-(tiintethylmethylenedioxy -A -pregnene-7a-0l-3,2O-dione monocyclic heterocyclic lower alkyl; and together with --.the, carbon to which they are joined P and Q is selected from the group consisting of a monocyclic cycloalkyl and monocyclic heterocyclic radical.

2. A compound of the formula wherein X is halogen; P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, mono- 5 6 cyclic aryl, monocyclic aryl lower alkyl, monocyclic 3. 604,70 oxido 10,2oz-II1CthYl6118-l60,l7ot-(dilll6thYlheterocyclic and monocyclic heterocyclic lower alkyl; Q methylenedioxy)-A -pregnene-3,20-dione. is selected from the group consisting of lower alkyl, halo 4. 6 chloro 1a-chloromethyl-l6u,17a-(dimethylrnethlower alkyl, monocyclic cycloalkyl, monocyclic cycloylenedioxy)-A -pregnadiene-3,ZO-dione. alkyl lower alkyl, inonocyclic aryl, monocyclic aryl lower 5 5. 6B chloro-1aim-methylene-l6a,l7a-(dimethylmethalkyl, monocyclic heterocyclic and monocyclic heteroylenedioxy)-A -pregnene-7a-ol-3,ZO-dione. cyclic lower alkyl; and together with the carbon to which they are joined P and Q is selected from the group con- N references it d,

sisting of a monocyclic cycloalkyl and monocyclic heterocyclic radical. 10 LEWIS GOTTS, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3,231 569 January 25, 1966 Gerald W. Krakower It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, for that portion of formulas (A)and (B) each occurrence, reading /O\ read /C\ same column 2, for that portion of formula (C) reading read column 4, lines 35 to 45, for that portion of the formula reading same column 4, lines 62 to 73, for that portion of the formula reading CH CH (3:0 read I= Signed and sealed this 13th day of December 1966.

(SEAL) Attest:

SWIDER EDWARD J. BRENNER ERNEST W. 0

Commissloner of Patents Attesting Officer 

2. A COMPOUND OF THE FORMULA 